Use of medicinal plants as a remedy against lymphatic filariasis: Current status and future prospect

Abstract Despite the successes achieved so far with the Global Programme to Eliminate Lymphatic Filariasis, there is still an appreciable number of lymphatic filarial patients who need alternative treatment and morbidity management strategies. The unresponsiveness of some cohorts to the drugs used in the mass drug administration program is currently raising a lot of questions and this needs urgent attention. Natural medicinal plants have a long‐standing history of being effective against most disease conditions. Countries such as India have been able to integrate their natural plant remedies into the treatment of lymphatic filarial conditions, and the results are overwhelmingly positive. Components of Azadirachta indica A. Juss, Parkia biglobosa, Adansonia digitata, and Ocimum spp have been shown to have anti‐inflammatory, anticancerous, and antimicrobial activities in animal models. Therefore, this review calls for attention toward the use of natural plant components as an alternate treatment against lymphatic filariasis to help reduce the World Health Organization's burden of providing drugs for people in need of treatment every year.


| INTRODUCTION
Lymphatic filariasis (LF) is a neglected tropical disease (NTD) that occurs when filarial parasites (Wuchereria bancrofti and Brugia spp) are transmitted to humans through mosquitoes ( Figure 1). LF is a vector-borne, long-standing chronic disease which is the second leading cause of long-term and permanent disability in the world. 1 This disease has been a public health concern, especially in Africa and South America. LF is caused by the lymph-dwelling nematode parasites; W. bancrofti, Brugia malayi, and Brugia timori. The filarial nematode W. bancrofti accounts for 91% of LF infections while B. malayi and B. timori are responsible for the remaining 10% in South and Southeast Asia. [2][3][4] The clinical manifestations of the LF include hydrocele and lymphedema (LE) (mainly known as elephantiasis).
The development of modern medicines for NTDs from phytochemicals is intrinsically less likely to fail through problems of toxicity or other side effects when the phytochemical lead compounds originate from plant species, which are part of certificated herbal treatments. 5 Many have been monitored over a number of years/decades in clinical use with significant number of patients, for health conditions which are more serious than the NTD against which the phytochemicals could also shows promising activity. The current World Health Organization's (WHO) drugs of choice for its mass drug administration (MDA) program are ivermectin (IVM), albendazole (ALB), and diethylcarbamazine (DEC). 6 These drugs are effective in reducing microfilariae but not effective in killing the adult worms or relieving individuals with morbidity. 7,8 Furthermore, there is repopulation of microfilariae in the host system 6-12 months after treatment, hence the need to take the drugs annually. DEC has also been reported to cause severe side effects such as fever, gastrointestinal disturbance, headache, malaise, and skin rash that reduce patient's compliance. 9 The pathology is known to progress due to elevated inflammatory processes that unfolds in the presence of filarial antigen. [10][11][12] Data from field trials have shown potency of some antibiotics (doxycycline and minocycline) against LF. 7,[13][14][15][16] This notwithstanding, these antibiotics have a longer regimen duration and do not support national treatment programs. Thus, there is still the need for more effective drugs with less adverse reaction, shorter regimen duration, and less cost to achieve WHO's aim of interrupting transmission and helping individuals with LF morbidity. Moreover, these antibiotics usually clear microfilaria with a delayed gradual effect on the early stages of pathology (hydrocele and LE).
The unavailability of vaccine and drugs for this condition increases the demand for cheap and orthodox methods which are antifilarial in nature. 17   ways including p53, NF-κB, and VEGF, but the exact molecular mechanism used by these constituents in the prevention of pathogenesis is not yet fully understood. Other studies have also confirmed its potency against filarial parasites and their vectors. 26,29 Neem is also known to have antimicrobial properties through its inhibitory effect on microbial growth by showing efficacies against Staphylococcus aureus and Methicillin-resistant Staphylococcus aureus (MRSA) with greatest zones of inhibition noted at 100% concentration. 26 Tannins and flavonoids are the major polyphenols present in the bark of the trunks of P. biglobosa. These constituents have shown to be effective in the treatment of inflammatory diseases. 30 This approach could be explored in the treatment of inflammatory conditions such as is seen in LF pathologies. Various parts of P.
biglobosa (family Fabaceae, locally called Dawadawa tree in Ghana) have good antimicrobial activities against some bacteria strains. 31 So far, there is still no clinical study conducted on the plants to investigate activity in most human diseases including LF. 31 With the inability of the filarial drugs to cure pathologies in LF, a look into this F I G U R E 2 Possible anti-inflammatory action of medicinal plants against lymphatic filariasis (LF). The pathogenesis of LF is proposed to be due mainly to elevated inflammatory cytokines (IL-1, TNF-⍺). Compounds from medicinal plants regulate this pathway by reducing inflammation thereby setting inflammation to levels that are not detrimental to one's health. Created with Biorender.com. Polysaccharides from Adansonia digitata purified through permeation chromatography have proven to be a potential antioxidant and anti-inflammatory food supplement. 33 It is paramount to reduce or regulate inflammation to levels that is tolerable for the body, therefore this plant and its components could help reduce elevated inflammation as seen in individuals with LF pathologies ( Figure 3). This inspired a study reporting on the efficacious therapeutic activity of Azadirachtin against LF. It further indicated that a significant tetranortriterpenoid phytocompound found in Azadirachta indica, showed efficacies against the filarial parasite Setaria cervi in vitro. 34 Thus, remedies for LF pathology should be directed towards interventions that are known to invoke less or moderate inflammation. Data has shown that not only are individuals with LF pathologies faced with unfathomable societal stigma and discrimination, also they experience acute filarial attacks due to systemic inflammation. Exploration of the baobab tree to ascertain the exact inflammatory pathways targeted by the constituents of the plant could help ameliorate this occurrence which is mostly at its peak in the wet/rainy seasons. 35 Essential oils from three Ocimum spp from the family Lamiaceae  36 This plant is locally known in Ghana as "Akoko mesa." It may be worthwhile to reinvestigate the potential of essential oils derived from other Ocimum sp for possible production of mosquito coils, which could substantially be utilized in repelling blood-seeking mosquitoes and break the vector-human contacts (Table 1).

| PHARMACOKINETICS OF PLANT MEDICINES AGAINST LF
There is an urgent need to expand the available pharmaceutical repertoire. This must be preceded by experiments on the potencies, activity doses, and toxicity of potential medicinal plants.
Studies on the antimicrobial activities of medicinal plants (neem oil extracts, P. biglobosa, etc) and phytochemicals using in-vitro methods (broth dilution, disc or agar diffusion, and agar overlay assays) are used to determine the minimum inhibitory concentration and minimum bactericidal concentration of each treatment. 30,32,37 Alternatively, in vivo model studies have been implemented to reflect human infections and disease testing; these models include intraperitoneal or intravenous injection, or oral or gastric administration of plant extracts in mice, rats, guinea pigs, and rabbits. 38 While thousands of people die each year from supposedly "safe" over-the-counter remedies, deaths or hospitalizations due to medicinal plants are so rare to find. This notwithstanding, the appropriate volume of medicinal plants whether used as food or supplement is of great concern in both humans and animals. A study reported pathological neurological disorders in horses following a large intake of fresh Bambusa vulgaris leaves. 39 Surprisingly, the aqueous extract of this same plant is a popular antimalarial medicine in Ghana. 40 Dye exclusion and MTT assay showed the potency of azadirachtin against S. cervi with a median lethal dose (LC 50 ) of 6.28 μg/mL for microfilariae (mf), and 9.55 μg/ mL for adult parasites. A mouse model study on the toxicity of neem trees showed that clinical dosage should be less than 1600 mg/kg/day to prevent organ damage. 41 Elsewhere, it has been concluded on the toxicity of P. biglobosa that 1800 mg/kg and 1600 mg/kg were the intraperitoneal lethal dose 50 (LD 50 ) for F I G U R E 3 Preventive chemotherapy (PC) coverage per year for lymphatic filariasis. aqueous extract from roasted and fermented seeds, respectively. 42 This implies nontoxic dose should be less than the above doses.
Moreover, after 60 min of oral administration of ethyl acetate extracts of Ocimum sp, mice with edeama experienced less inflammation. 43 46 Study has also shown that aqueous extracts of neem leaves have wound-healing ability and this is an appropriate option, preferred for its naturality, ease of access, and is safe, with no known adverse effect. 47    writing-review and editing.

ACKNOWLEDGMENTS
We would like to acknowledge the authors of the referenced studies.